The major goal of this project is to investigate the cellular and molecular mechanisms that link sepsis and lung injury in two situations: a) when an intrapulmonary infection is the primary source of the sepsis; and b) when a nonpulmonary intraabdominal focus is the primary source of sepsis. Our major hypothesis is that when inflammatory reactions begin in the lungs, the inflammatory reaction is relatively compartmentalized and lung injury occurs almost immediately, whereas evidence of systemic inflammation is delayed. When inflammatory reactions begin in the systemic circulation, particularly in the bowel or peritoneal cavity, the lungs are involved later, as a consequence of bacterial products from the site of infection and proinflammatory products that are produced in the liver and drain to the lungs. We will compare rabbits with primary lung injury caused by E. coli or E. coli endotoxin (LPS), with rabbits with a primary intraabdominal focus of infection. We will compare parameters of inflammation and endothelial injury in blood vs parameters of inflammation and epithelial injury in the lungs. Intravascular parameters will include: a) cytokine gene expression by blood leukocytes; b) activation of blood neutrophils; c) a circulating marker of endothelial injury, Von Willebrand's factor (VWF); and d) the production of LBP, an endotoxin binding protein that enhances the sensitivity of effected cells to LPS. Lung parameters will include: a) changes in lung epithelial permeability; b) inflammatory cell accumulation in lung lavage fluid (BAL); and 3) the accumulation of LBP and proinflammatory cytokines in BAL, including TNFalpha, IL1beta, IL8, MCP-1 and others. We also will compare the evolution of cytokine expression in blood leukocytes, liver and lung tissue using immunocytochemistry. Finally, we will investigate the effects of new treatment protocols on the evolution of the inflammatory response and lung injury in these animal models. These studies will improve our understanding of the evolution of lung injury and they will help to plan the timing of new therapies in humans and the selection of subgroups in which these therapies might be beneficial.